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Immune regulation by dead intestinal epithelial cells

Research Project

Project/Area Number 17H04052
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionTokyo University of Pharmacy and Life Science

Principal Investigator

ASANO Kenichi  東京薬科大学, 生命科学部, 准教授 (10513400)

Co-Investigator(Kenkyū-buntansha) 濱田 理人  筑波大学, 医学医療系, 助教 (20567630)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
KeywordsCCL8 / 炎症性腸疾患 / 死細胞 / DAMPs / マクロファージ / ビメンチン / hnRNP / 腸管免疫 / 細胞死 / CD169 / 大腸炎 / 腸炎 / 炎症
Outline of Final Research Achievements

We found that tBHP-treated adult mouse small intestinal epithelial cell (aMos7)-derived conditioned medium (CM) enhances CCL8 production by macrophages that were stimulated in vitro with LPS. The CM alone did not induce CCL8 production by macrophages. These findings suggest that a dead cell-derived factor and bacterial components coordinately promote intestinal inflammation. To identify this dead cell-derived molecule, we fractioned CM from tBHP-treated aMos7 cells by HPLC on sizing column monitored with an ultraviolet spectrum detector. A fraction (approximately 1,000 kDa) that showed CCL8 enhancing activity were further separated by HPLC with a reverse phase (C18) column. Mass spectrometry identified Vimentin and hnRNPa1b2-derived peptides that are known as potential endogenous adjuvants. Role of these molecules in the induction of CCL8 by macrophages will be examined by generating Vimentin- or hnRNPa2b1-knock-down aMos7 cells by CRISPR/Cas9 method.

Academic Significance and Societal Importance of the Research Achievements

近年わが国で炎症性腸疾患の罹患者数が急増しており、新たな治療標的の発見が望まれている。以前に我々は、腸管のCD169マクロファージがCCL8を産生し、腸炎進展に関与することを発見した。抗CCL8抗体はマウスの大腸炎を抑制したことから、マクロファージによるCCL8産生の制御が、炎症性腸疾患の治療戦略策定に寄与すると考え、CCL8産生を促進するシグナル分子同定を目指した。本研究では、腸上皮死細胞から産生される内因性アジュバントが、マクロファージによるCCL8産生を促進することを証明した。今後、これらの分子を同定することで、炎症性腸疾患の急性増悪機序の理解や、治療法開発に役立つことが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (18 results)

All 2020 2019 2018 2017

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 4 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Early Fate Defines Microglia and Non-parenchymal Brain Macrophage Development2020

    • Author(s)
      Utz Sebastian G.、See Peter、Mildenberger Wiebke、Thion Morgane Sonia、Silvin Aymeric、Lutz Mirjam、Ingelfinger Florian、Rayan Nirmala Arul、Lelios Iva、Buttgereit Anne、Asano Kenichi、Prabhakar Shyam、Garel Sonia、Becher Burkhard、Ginhoux Florent、Greter Melanie
    • Journal Title

      Cell

      Volume: 181 Issue: 3 Pages: 557-573.e18

    • DOI

      10.1016/j.cell.2020.03.021

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Usp18 Expression in CD169+ Macrophages is Important for Strong Immune Response after Vaccination with VSV-EBOV2020

    • Author(s)
      Friedrich Sarah-Kim、Schmitz Rosa、Bergerhausen Michael、Lang Judith、Cham Lamin B.、Duhan Vikas、H?ussinger Dieter、Hardt Cornelia、Addo Marylyn、Prinz Marco、Asano Kenichi、Lang Philipp Alexander、Lang Karl Sebastian
    • Journal Title

      Vaccines

      Volume: 8 Issue: 1 Pages: 142-142

    • DOI

      10.3390/vaccines8010142

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MT1-MMP recruits the ER-Golgi SNARE Bet1 for efficient MT1-MMP transport to the plasma membrane.2019

    • Author(s)
      Miyagawa, T.,* Hasegawa, K.,* Aoki, Y.,* Watanabe, T.,* Otagiri, Y., Arasaki, K., Wakana, Y., Asano, K., Tanaka, M., Yamaguchi, H., Tagaya, M. and Inoue, H. (*, These authors contributed equally to this work.)
    • Journal Title

      J. Cell Biol.

      Volume: 218 Issue: 10 Pages: 3355-3371

    • DOI

      10.1083/jcb.201808149

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Maf expression in human macrophages and lymph node sinus macrophages in patients with esophageal cancer2019

    • Author(s)
      Takeya Hiroto、Ohnishi Koji、Shiota Takuya、Saito Yoichi、Fujiwara Yukio、Yagi Taisuke、Kiyozumi Yuki、Baba Yoshifumi、Yoshida Naoya、Asano Kenichi、Tanaka Masato、Baba Hideo、Komohara Yoshihiro
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 59 Issue: 3 Pages: 112-118

    • DOI

      10.3960/jslrt.19002

    • NAID

      130007720030

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage Niche2019

    • Author(s)
      Camara Abdouramane、Cordeiro Olga G.、Alloush Farouk、Sponsel Janina、Chypre M?lanie、Onder Lucas、Asano Kenichi、Tanaka Masato、Yagita Hideo、Ludewig Burkhard、Flacher Vincent、Mueller Christopher G.
    • Journal Title

      Immunity

      Volume: 50 Issue: 6 Pages: 1467-1481.e6

    • DOI

      10.1016/j.immuni.2019.05.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury2018

    • Author(s)
      Ikeda Naoki、Asano Kenichi、Kikuchi Kenta、Uchida Yoshimi、Ikegami Hiroki、Takagi Ryo、Yotsumoto Satoshi、Shibuya Takumi、Makino-Okamura Chieko、Fukuyama Hidehiro、Watanabe Takashi、Ohmuraya Masaki、Araki Kimi、Nishitai Gen、Tanaka Masato
    • Journal Title

      Science Immunology

      Volume: 3 Issue: 28

    • DOI

      10.1126/sciimmunol.aat0207

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice.2018

    • Author(s)
      Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H.
    • Journal Title

      Biochemical Biophysical Research Communications

      Volume: 505 Issue: 2 Pages: 453-459

    • DOI

      10.1016/j.bbrc.2018.09.128

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation2018

    • Author(s)
      Kikuchi Kenta、Iida Mayumi、Ikeda Naoki、Moriyama Shigetaka、Hamada Michito、Takahashi Satoru、Kitamura Hiroshi、Watanabe Takashi、Hasegawa Yoshinori、Hase Koji、Fukuhara Takeshi、Sato Hideyo、Kobayashi Eri H.、Suzuki Takafumi、Yamamoto Masayuki、Tanaka Masato、Asano Kenichi
    • Journal Title

      The Journal of Immunology

      Volume: 201 Issue: 2 Pages: 635-651

    • DOI

      10.4049/jimmunol.1800040

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Neutrophils convert into atypical Ly6G+SiglecF+ cells with neurosupportive properties in olfactory neuroepithelium2019

    • Author(s)
      小川慶、浅野謙一、田中正人
    • Organizer
      第48回 日本免疫学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Immunoregulatory Ym1+Ly6Chi monocytes expand in the bone marrow during the late phase of inflammation and accelerate tissue repair.2019

    • Author(s)
      Kenichi Asano, Naoki Ikeda, Kenta Kikuchi, Masato Tanaka
    • Organizer
      Keystone Symposia
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Phenotypic conversion of intestinal CD169+ macrophages by Maf2019

    • Author(s)
      Kenta Kikuchi, Masato Tanaka, Kenichi Asano
    • Organizer
      Keystone Symposia
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Phenotypic conversion of tissue macrophages by Maf2018

    • Author(s)
      Kenichi Asano, Kenta Kikuchi, Masato Tanaka
    • Organizer
      Australia-Japan Meeting on Cell Death
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Phenotypic conversion of the colon macrophage phenotype by Maf2018

    • Author(s)
      Kenichi Asano
    • Organizer
      第91回 日本生化学会大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Mafによる組織マクロファージの形質変化2018

    • Author(s)
      浅野謙一
    • Organizer
      第27回 日本Cell death学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] A transcription factor c-Maf acts as the molecular switch that converts CD169+ macrophage phenotype2017

    • Author(s)
      K. Kikuchi, M. Tanaka, and K. Asano
    • Organizer
      5th Annual Meeting of the Intenational Cytokine & Interferon Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 転写因子c-MafによるCD169陽性マクロファージの形質制御2017

    • Author(s)
      菊池 健太、田中 正人、浅野 謙一
    • Organizer
      日本生化学会 関東支部会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 大腸炎を誘導する腸管マクロファージのサブセット2017

    • Author(s)
      浅野 謙一、菊池 健太、田中 正人
    • Organizer
      日本薬学会 関東支部会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Patent(Industrial Property Rights)] 免疫調節作用を有する単球細胞及びその使用方法2018

    • Inventor(s)
      浅野謙一、西躰元、田中正人
    • Industrial Property Rights Holder
      浅野謙一、西躰元、田中正人
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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